A trimeric structural fusion of an antagonistic tumor necrosis factor-alpha mutant enhances molecular stability
| Project/Area Number |
16K18918
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Drug development chemistry
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| Research Institution | Kobe Gakuin University |
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Principal Investigator |
Inoue Masaki 神戸学院大学, 薬学部, 助手 (80757097)
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| Research Collaborator |
TSUNODA Shinichi
KAMADA Haruhiko
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| Project Period (FY) |
2016-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 腫瘍壊死因子 / TNF / アンタゴニスト / TNFR1 / 自己免疫疾患 / 一本鎖化 / 構造最適化 / 蛋白質工学 / 機能性人工タンパク質 / 最適化 |
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| Outline of Final Research Achievements |
We have been investigating the use of TNFR1-selective antagonistic TNF mutant (R1antTNF) to reveal the pharmacological effect of TNFR1-selective inhibition as a new therapeutic modality. This study aimed to further improve and optimize the activity and behavior of this mutant protein both in vitro and in vivo. Especially, we examined a trimeric structural fusion of R1antTNF, formed via the introduction of short peptide linkers, as a strategy to enhance bioactivity and molecular stability. The trimeric fusion, referred to as single-chain R1antTNF (scR1antTNF), was found to retain in vitro molecular properties of receptor selectivity and antagonistic activity but displayed a marked increase in thermal stability. Furthermore, molecular modification of scR1antTNF using polyethylene glycol (PEG) significantly prolonged the residence time in vivo. Therefore, scR1antTNF is considered useful for therapeutic drug application.
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Report
(3 results)
Research Products
(11 results)
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[Journal Article] A trimeric structural fusion of an antagonistic tumor necrosis factor-α mutant enhances molecular stability and enables facile modification2017
Author(s)
Masaki Inoue, Daisuke Ando, Haruhiko Kamada, Shintaro Taki, Mayumi Niiyama, Yohei Mukai, Takashi Tadokoro, Katsumi Maenaka, Taisuke Nakayama, Yuji Kado, Tsuyoshi Inoue, Yasuo Tsutsumi and Shin-ichi Tsunoda
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Journal Title
J. Biol. Chem.,
Volume: in press
Issue: 16
Pages: 235-237
DOI
Related Report
Peer Reviewed / Open Access
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